CD19 is a major B cell receptor–independent activator of MYC-driven B-lymphomagenesis

PAX5, a B cell–specific transcription factor, is overexpressed through chromosomal translocationsin a subset of B cell lymphomas. Previously, we had shown that activation of immunoreceptor tyrosine-based activation motif( ITAM) proteins and B cell receptor(BCR) signaling by PAX5contributes to B-lymphomagenesis. However, the effect of PAX5on other oncogenic transcription factor-controlled pathways is unknown. Using a MYC-induced murine lymphoma model as well as MYC-transformed human B cell lines, we found that PAX5controls c-MYC protein stability and steady-state levels. This promoter-independent, posttranslational mechanism of c-MYC regulation was independent of ITAM/BCR activity. Instead it was controlled by another PAX5target, CD19, through the PI3K-AKT-GSK3β axis. Consequently, MYC levels in B cells from CD19-deficient mice were sharply reduced. Conversely, reexpression of CD19in murine lymphomas with spontaneous silencing of PAX5boosted MYC levels, expression of its key target genes, cell proliferation in vitro, and overall tumor growth in vivo. In human B-lymphomas, CD19mRNA levels were found to correlate with those of MYC-activated genes. They also negatively correlated with the overall survival of patients with lymphoma in the same way that MYC levels do. Thus, CD19is a major BCR-independent regulator of MYC-driven neoplastic growthin B cell neoplasms.